In human pregnancies mothers and their embryo/fetuses are invariably genetically different. Thus, attenuation of the adaptive maternal immune response, which is programmed to reject 'foreign' entities, is required for pregnancy to be initiated and maintained. Unexpectedly, given the propensity of the immune system to dispose of non-self entities, at least 50% of expected human pregnancies reliably go forward. This indicates that to a large extent, effective systems of tolerance have evolved. Although overlapping and redundant mechanisms of tolerance have been identified, production of HLA-G by trophoblast cells derived from the external trophectoderm layer of the blastocyst appears to be of major importance. At this point in time, no pregnancies in which all of the proteins derived from the HLA-G gene are absent have as yet been reported. Many studies have shown that both membrane-bound and soluble isoforms of the proteins derived from this HLA class Ib gene are produced by placental trophoblast cells, with consequences that include but are not restricted to immune suppression at the maternal-fetal interface. Here we report new studies that are leading to a better understanding of the HLA-G proteins, their unique structures, unusual modes of regulation, diverse functions, and potential for use in diagnostic and therapeutic procedures related to suboptimal fertility in women.